RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer
Abstract Background The RNA-binding protein Musashi-2 (MSI2) has been implicated in the tumorigenesis and tumor progression of some human cancers. MSI2 has also been reported to suppress tumor epithelial-to-mesenchymal transition (EMT) progression in breast cancer, and low MSI2 expression is associa...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-05-01
|
| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-020-01587-x |
| _version_ | 1818033087504711680 |
|---|---|
| author | Ming Li An-qi Li Shu-ling Zhou Hong Lv Ping Wei Wen-tao Yang |
| author_facet | Ming Li An-qi Li Shu-ling Zhou Hong Lv Ping Wei Wen-tao Yang |
| author_sort | Ming Li |
| collection | DOAJ |
| description | Abstract Background The RNA-binding protein Musashi-2 (MSI2) has been implicated in the tumorigenesis and tumor progression of some human cancers. MSI2 has also been reported to suppress tumor epithelial-to-mesenchymal transition (EMT) progression in breast cancer, and low MSI2 expression is associated with poor outcomes for breast cancer patients; however, the underlying mechanisms have not been fully investigated. This study investigated the expression and phenotypic functions of two major alternatively spliced MSI2 isoforms (MSI2a and MSI2b) and the potential molecular mechanisms involved in triple-negative breast cancer (TNBC) progression. Methods The Illumina sequencing platform was used to analyze the mRNA transcriptomes of TNBC and normal tissues, while quantitative reverse transcription-polymerase chain reaction and immunohistochemistry validated MSI2 isoform expression in breast cancer tissues. The effects of MSI2a and MSI2b on TNBC cells were assayed in vitro and in vivo. RNA immunoprecipitation (RIP) and RNA sequencing were performed to identify the potential mRNA targets of MSI2a, and RIP and luciferase analyses were used to confirm the mRNA targets of MSI2. Results MSI2 expression in TNBC tissues was significantly downregulated compared to that in normal tissues. In TNBC, MSI2a expression was associated with poor overall survival of patients. MSI2a overexpression in vitro and in vivo inhibited TNBC cell invasion as well as extracellular signal-regulated kinase 1/2 (ERK1/2) activity. However, MSI2b overexpression had no significant effects on TNBC cell migration. Mechanistically, MSI2a expression promoted TP53INP1 mRNA stability by its interaction with the 3′-untranslated region of TP53INP1 mRNA. Furthermore, TP53INP1 knockdown reversed MSI2a-induced suppression of TNBC cell invasion, whereas ectopic expression of TP53INP1 and inhibition of ERK1/2 activity blocked MSI2 knockdown-induced TNBC cell invasion. Conclusions The current study demonstrated that MSI2a is the predominant functional isoform of MSI2 proteins in TNBC, that its downregulation is associated with TNBC progression and poor prognosis and that MSI2a expression inhibited TNBC invasion by stabilizing TP53INP1 mRNA and inhibiting ERK1/2 activity. Overall, our study provides new insights into the isoform-specific roles of MSI2a and MSI2b in the tumor progression of TNBC, allowing for novel therapeutic strategies to be developed for TNBC. |
| first_indexed | 2024-12-10T06:17:41Z |
| format | Article |
| id | doaj.art-e3baa13c46f5403e8f1b7bf1fef8eb1d |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-10T06:17:41Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-e3baa13c46f5403e8f1b7bf1fef8eb1d2022-12-22T01:59:24ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662020-05-0139111810.1186/s13046-020-01587-xRNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancerMing Li0An-qi Li1Shu-ling Zhou2Hong Lv3Ping Wei4Wen-tao Yang5Department of Pathology, Fudan University Shanghai Cancer CenterDepartment of Pathology, Fudan University Shanghai Cancer CenterDepartment of Pathology, Fudan University Shanghai Cancer CenterDepartment of Pathology, Fudan University Shanghai Cancer CenterDepartment of Pathology, Fudan University Shanghai Cancer CenterDepartment of Pathology, Fudan University Shanghai Cancer CenterAbstract Background The RNA-binding protein Musashi-2 (MSI2) has been implicated in the tumorigenesis and tumor progression of some human cancers. MSI2 has also been reported to suppress tumor epithelial-to-mesenchymal transition (EMT) progression in breast cancer, and low MSI2 expression is associated with poor outcomes for breast cancer patients; however, the underlying mechanisms have not been fully investigated. This study investigated the expression and phenotypic functions of two major alternatively spliced MSI2 isoforms (MSI2a and MSI2b) and the potential molecular mechanisms involved in triple-negative breast cancer (TNBC) progression. Methods The Illumina sequencing platform was used to analyze the mRNA transcriptomes of TNBC and normal tissues, while quantitative reverse transcription-polymerase chain reaction and immunohistochemistry validated MSI2 isoform expression in breast cancer tissues. The effects of MSI2a and MSI2b on TNBC cells were assayed in vitro and in vivo. RNA immunoprecipitation (RIP) and RNA sequencing were performed to identify the potential mRNA targets of MSI2a, and RIP and luciferase analyses were used to confirm the mRNA targets of MSI2. Results MSI2 expression in TNBC tissues was significantly downregulated compared to that in normal tissues. In TNBC, MSI2a expression was associated with poor overall survival of patients. MSI2a overexpression in vitro and in vivo inhibited TNBC cell invasion as well as extracellular signal-regulated kinase 1/2 (ERK1/2) activity. However, MSI2b overexpression had no significant effects on TNBC cell migration. Mechanistically, MSI2a expression promoted TP53INP1 mRNA stability by its interaction with the 3′-untranslated region of TP53INP1 mRNA. Furthermore, TP53INP1 knockdown reversed MSI2a-induced suppression of TNBC cell invasion, whereas ectopic expression of TP53INP1 and inhibition of ERK1/2 activity blocked MSI2 knockdown-induced TNBC cell invasion. Conclusions The current study demonstrated that MSI2a is the predominant functional isoform of MSI2 proteins in TNBC, that its downregulation is associated with TNBC progression and poor prognosis and that MSI2a expression inhibited TNBC invasion by stabilizing TP53INP1 mRNA and inhibiting ERK1/2 activity. Overall, our study provides new insights into the isoform-specific roles of MSI2a and MSI2b in the tumor progression of TNBC, allowing for novel therapeutic strategies to be developed for TNBC.http://link.springer.com/article/10.1186/s13046-020-01587-xTriple-negative breast cancerMSI2IsoformsTP53INP1Metastasis |
| spellingShingle | Ming Li An-qi Li Shu-ling Zhou Hong Lv Ping Wei Wen-tao Yang RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer Journal of Experimental & Clinical Cancer Research Triple-negative breast cancer MSI2 Isoforms TP53INP1 Metastasis |
| title | RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer |
| title_full | RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer |
| title_fullStr | RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer |
| title_full_unstemmed | RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer |
| title_short | RNA-binding protein MSI2 isoforms expression and regulation in progression of triple-negative breast cancer |
| title_sort | rna binding protein msi2 isoforms expression and regulation in progression of triple negative breast cancer |
| topic | Triple-negative breast cancer MSI2 Isoforms TP53INP1 Metastasis |
| url | http://link.springer.com/article/10.1186/s13046-020-01587-x |
| work_keys_str_mv | AT mingli rnabindingproteinmsi2isoformsexpressionandregulationinprogressionoftriplenegativebreastcancer AT anqili rnabindingproteinmsi2isoformsexpressionandregulationinprogressionoftriplenegativebreastcancer AT shulingzhou rnabindingproteinmsi2isoformsexpressionandregulationinprogressionoftriplenegativebreastcancer AT honglv rnabindingproteinmsi2isoformsexpressionandregulationinprogressionoftriplenegativebreastcancer AT pingwei rnabindingproteinmsi2isoformsexpressionandregulationinprogressionoftriplenegativebreastcancer AT wentaoyang rnabindingproteinmsi2isoformsexpressionandregulationinprogressionoftriplenegativebreastcancer |